Halogenation of 3-keto steroids



United States Patent HALOGENATION OF 3-KETO STEROIDS John T. Day, Danville, Pa., assignor to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Application November 1, 1956 Serial No. 619,663

13 Claims. (Cl. 260-39745) This invention relates to a halogenation process and particularly to an improved process for the halogenation of steroids to produce the corresponding 4-halo-steroid.

This application is a continuation-in-part of my copending application, Serial No; 438,618, filed June 22,

1954, now abandoned. The discovery of the remarkable therapeutic properties of cortisone, hydrocortisone and similar related compounds h-as stimulated wide interest in finding simpler and to the development of various methods of halogenating the 4-position of steroids. Considerable efiort on the part n u "of the steroid chemists has been expended over a period of years in an effort to improve the yield and quality of these halogenated products. Variations in reaction conditions such as time, temperature and mode of addition of reactants have increased the yield of pure products by small increments to approximately 70%. In order to achieve such a yield it has been necessary to treat a solution of the steroid in acetic acid with an equimolar amount of bromine in the presence of a small quantity of hydrogen bromide as a catalyst.

The halogenation reaction is a nonselective one and as such is subject to certain disadvantages with consequent complications in operations and handling and a relatively low yield. The disadvantages are apparent, considering that this step occurs nearly at the end of a long and involved synthesis which requires the employment of expensive starting material, a multiplicity of chemical equipment, reagents and solvents. It is obvious therefore that any increase in yield or simplification of operations at this pointin the synthesis of the various halogenated steroids is extremely advantageous.

A primary object of the present invention is to provide an improved process for the production of 4-halo-3-ketopregnanes of the normal series, in which the hydrogen atom attached to the 5carbon atom is in the beta position.

A related object is to provide such a process which will result in nearly quantitative yields of 4-halo-3-ketopregnanes. Other, objects and the advantages of this invention will be apparent-from the detailed description hereinafter provided.

According to the present invention, it has been discovered that 4-halo-3-ketopregnane compounds of the normal series having a 53 hydrogen atom may be prepared in approximately quantitative yield by carrying out the halogenation of 3-ketopregnane compound at a temperature lower than -30 C. and preferably from 2,907,776 Patented Oct. 6, 1959 the, production of 4-halo-3-ketosteroids in very high yields. It also permits the recovery of a product in a high degree of purity by substantially eliminating the formation of undesirable by-products, such as, the 2-halo and 2,4dihalo-derivatives.

The starting materials for the process: of the invention are the 3-ketosteroids and particularly the 3-ketopregnanes such as 17a-hydroxy-3-ketopregnanes. The starting materials have a 4-methylene group; i.e. they are unsubstituted at the 4 position. The process can also be applied effectively to these steroids containing other functional substituents attached to the steroid nucleus. Thus, keto groups may be present such as at the 11 and 20 positions, hydroxy groups at the 11, 17 and 21 positions and acyloxy groups such as at the 21 position. Representative of such steroids which may be converted to the corresponding 4-halo-3-ketosteroids by this invention are pregnanc- 17u,21 diol 3,11,20 trione 21 acetate; pregnanc- 17cc,2l diol 3,20 dione 21 acetate; pregnane 21 ol 3,20 dione 21 acetate; pregnane 21 o1-3,ll,20- trione 21 acetate; pregnane 11,6,17,21 triol 3,20 dione 21 acetate; pregnane 3,11,20 trione; pregnane 3,20 dione; pregnane 11,17,20,321 tetraol 3 4 one; pregnane 17,20,21 triol 3 one; pregnane-- lloc,17ot diol 3,20 dione; pregnane 17a,ZO,2l triol 3 one 20,21 diacetate; and pregnane 170:,21 diol 3,11,20 trione 21 benzoate.

The halogenating agent is a halogen of atomic weight 35 or 80, consisting of chlorine and bromine. The halogenation is preferably carried out by dissolving or suspending the steroid in a solvent, such as a polar organic solvent. Typical examples of suitable solvents are methylene chloride, ethylene dichloride, chlorof0rrn,is0- propanol, acetonitrile, and mixtures of solvents such as acetic acid-chloroform, methylene dichloride-acetic acid, ethylene dichloride-acetic acid, isopropanol-acetonitrileacetic acid, acetonitrile-acetic acid and acetic acid-acetic .anhydride.

1 It is usually desirable to add a catalyst to the reaction mixture to promote the rate of reaction. The halogenation catalyst mustbe one which is operative at the low temperatures of this invention. The most common of these is hydrogen bromide. The catalyst is usually used in 10 to 120 mole percent of the steroid.

The halogenating agent may be supplied to the reac- ;tion mixture in any suitable manner. It is preferred. to

add an equimolar quantity of halogen. Precise control of the amount of halogen is not necessary, however, as the only halogenation reaction occurring at temperatures C. is at the 4 position. No halogenation occursat other positions, even when excess halogen is present.

In a preferred mode of operation a B-keto-pregnane is dissolved in a mixture of chloroform and acetic acid and cooled to 50 C. Thereafter approximately 10 mole percent ofhydrogen bromide in acetic acid is'added followed by the addition of about 100* mole percent each of bromine and hydrogen bromide in acetic acid. It is understood that other modes of operation may also be used. The reaction temperature is maintained in a range of- 40 to C. Under these conditions the reaction is complete in about one hour.

Upon completion of the reaction, it is desirable to neutralize the hydrogen bromide formed with a base such as sodium acetate or sodium bicarbonate. It is also desirable to discharge any excess bromine which A solution of 100 g. (0.2478 mole) of pregnane-17u,

21-diol-3,11,20-trione-21-acetate in 280 ml. of acetic acid and 2250 m1. of choloroform is cooled to 55 C. A ,solution of 0.248 mole hydrogen bromide and 0.2402

mole of bromine in 248 ml. of acetic acid is added over a period of 60 minutes while maintaining the tempera ture at -55 to 60 C. The color disappears after an additional 45 minutes at 65 C. 'The reaction mixture is agitated with a solution of 40.25 g. of sodium acetate in 333 cc. of water. The chloroform is removed by distillation under reduced pressure. Water is added to a final volume of 4.5 l. The slurry is aged at C. for 60 minutes, filtered and the filter cake washed free of acid and salts with water. The product, 4-bromo-pregnane-l7oc,21-diol-3,11,20-trione-21-acetate, having a rotation of [a] plus 101.5 (acetone), is recovered in 98.2 percent yield.

Example 2 A solution of 100 g. (0.2478 mole) of pregnane-l7a, 21-diol-3,11,20-trione-21-acetate in 1000 ml. of isopropanol and 1500 ml. of acetonitrile is cooled to -40 C. A solution of 0.496 mole of hydrogen bromide and 0.247

.mole of bromine in 465 m]. of acetic acid is added over a period of 60 minutes while maintaining the temperature of the solution at 40 C. The procedure described in Example 1 is then followed yielding 95.1% of 4-bromopregnane-17a,21-diol-3,11,20-trione-21-acetate having a rotation of [a] plus 100.40 (acetone).

Example 3 ture of the solution at -40 C. The procedure described in Example 1 is then followed yielding 95.6% of 4- .bromo-pregna'ne-lhfil-diol-3 ,11,20-trione-21-acetate.

Example 4 The procedure of Example 1 is followed except that chlorine is used in place of the bromine. The resulting product 4-chloro-pregnane-17a,21-diol-3,11,20-trione-21- acetate is obtained in equally high yield.

Example 5 Following the procedure given in Example 1, relatively pure 4-bromo-pregnane-170,21-diol-3,20-dione-21- acetate is prepared in high yield by the bromination of pregnane-l7a,21-diol-3,20-dione-2l-acetate.

Example 6 Following the procedure given in Example 1; relatively pure 4-brorno-pregnane-11p,l7ot,21-triol-3,20-dione-21-acetate is prepared in high yield by the bromination of pregnane-l1,17u,2l-triol-3,20-dione-21-acetate.

Example 7 "Following the procedure given in Example 1, relatively pure 4-bromo-pregnane-17a-ol-3,11,20-trione is prepared in high yield by the bromination of pregnane- 170t-O1-3,11,20-t1'l011.

Example 8 Following the procedure given in Example 1, relatively pure 4-bromo-pregnane-11a,17a,21-triol-3,20-dione-Zl-acetate is prepared in high yield by the bromination of pregnane-l1u,17a,21-ttiol-3,20-d.ione-21-acetate.

Example 9 Following the procedure given in Example 1, relatively pure 4-bromo-pregnane-21-ol-3,11,20-trione-21-acetate is prepared from pregnane 21-ol-3,1l,20-trione-21- acetate.

Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

What is claimed is: p

i. In a process for the halogenation of a 17u-hydroxy- 3-ketopregnane of the normal series which is unsubstituted at the 4 position to introduce a halogen atom into the 4-position thereof by reacting the 17a-hydroxy-3- ketopregnane with a halogen of atomic weight from 35 to 80, the step of conducting the halogenation at a ternperature lower than -30 C. in the presence of a hydrogen bromide catalyst.

2. In a process for the bromination of a 17a-hydroxy- 3-ketopregnane of the normal series which is unsubstituted at the 4 position to introduce a bromine atom into the 4-position thereof by reacting the 17a-hydroxy-3- ketopregnane with bromine, the step of conducting the bromination at a temperature of about -40 C. to about --70 C. in the presence of a hydrogen bromide catalyst.

3. In a process for the chlorination of a'17cx-hydroxy- 3-ketopregnane of the normal series which is unsubstituted at the 4 position to introduce a chlorine atom into the 4-position thereof by reacting the 17a-hydroxy-3- ketopregnane with chlorine, the step of conducting the chlorination at a temperature of about 40 C. to about --70 C. in the presence of a hydrogen bromide catalyst.

4. A process for the production of a 4-halo-17m-hydroxy-3,20-diketopregnane of the normal series which comprises reacting together approximately equimolar amounts of a 17u-hydroxy-3,20-diketopregnane which is unsubstituted at the 4 position and a halogen of atomic weight from 35 to in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about 40 C. to about 70 C.

5. A process for the production of a 4-halopregnane- 17a,21-diol-3,11,20-trione 21-acetate, which comprises reacting together approximately equimolar amounts of pregnane-17a,21-diol-3,11,20-trione 2l-acetate and a halogen of atomic weight from 35 to 80 in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about -40 C. to about -70 C.

6. A process for the production of a 4-halopregnane- 17a,21-(llOl-3,20-dl011 21-acetate, which comprises reacting together approximately equimolar amounts of pregnane-17m,21-diol-3,20-dione 2l-acetate and a halogen of atomicweight from 35 to 80 in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about -40 C. to about 70 C.

7. A process for the production of a 4-halopregnane- 11B,17a,21-tri0l-3,20-dione Zl-acetate, which comprises reacting together approximately equimolar amounts of pregnane-l1B,17a,21-triol-3,20-dione 21-acetate and a halogen of atomic weight from 35 to 80 in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about 40 C. to about -70 C.

8. A process for the production of a 4-halopregnane- 17ot-ol-3,1l,20-trione, which comprises reacting together approximately equimolar amounts of pregnane-l7a-ol-3, 11,20-trione and a halogen of atomic weight from 35 to 80 in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about .40 C. to about 70" C.

9. A process for the production of a 4-halopregnane- 21-ol-3,11,20-trio-ne 21-acetate, which comprises reacting together approximately equimolar amounts of pregnanc- 21ol-3,11,20-trione 21-acetate and a halogen of atomic weight from 35 to 80 in the presence of a solvent and a hydrogen bromide halogenation catalyst at a temperature of about 40 C. to about -.-70 C.

10. The process of claim 4 wherein the solvent is a 12. The process of claim 4 wherein the solvent is a 5 mixture of acetonitrile and acetic acid.

13. The process of claim 4 wherein hydrogen bromide and the halogen is hr the solvent is a acetic acid.

the catalyst is References Cited in the file of this patent UNITED STATES PATENTS Archer -s= June 15, I954 Schock et a1. 2-4 July 27, 1954 Djerassi et al. .t Mar. 29, 1955 Magerlein et al. Dec. 4, 1956 Djerassi et a1. Aug. 13, '1957 

1. IN A PROCESS FOR THE HALOGEANTION OF A 17A-HYDROXY3-KETOPREGNANE OF THE NORMAL SERIES WHICH IS UNSUBSTITUTED AT THE 4 POSITION TO INTRODUCE A HALOGEN ATOM INTO THE 4-POSITION THEREOF BY REACTING THE 17A-HYDROXY-3KETOPREGNANE WITH A HALOGEN OF ATOMIC WEIGHT FROM 35 TO 80, THE STEP OF CONDUCTING THE HALOGENATION AT A TEMPERATURE LOWER THAN -30*C. IN THE PRESENCE OF A HYDROGEN BROMIDE CATALYST. 